1. Field of the Invention
This invention relates to 5-HT.sub.4 receptor modulators, particularly 5-HT.sub.4 receptor antagonists, especially certain dihydrobenzodioxine carboxamide and ketone derivatives, and associated pharmaceutical compositions containing them and methods for their use as therapeutic agents.
2. Background of the Invention
Serotonin, a neurotransmitter with mixed and complex pharmacological characteristics, was first discovered in 1948 and has since been the subject of substantial research. Serotonin, also referred to as 5-hydroxy-tryptamine (5-HT), acts both centrally and peripherally on discrete 5-HT receptors. The 5-HT receptor family is presently delineated into seven major subclassifications, 5-HT.sub.1, 5-HT.sub.2, 5-HT.sub.3, 5-HT.sub.4, 5-HT.sub.5, 5-HT.sub.6, and 5-HT.sub.7, each of which may a heterogeneous.
The 5-HT.sub.4 receptors are widely distributed throughout the body and have various functions. For example, the 5-HT.sub.4 receptors located on postganglionic parasympathetic autonomic efferent neurons of the urinary bladder mediate facilitation of neurogenic bladder detrusor contractions (see Ford, A. P. D. W. and Kava, M. S., 5-HT4 Receptors in the Brain and Periphery, Eglen, R. M., Ed., Springer-Verlag Berlin and R.G. Landes Company Georgetown, Tex., 1998, pp 171-193; Waikar, M. V. etal., Br. J. Pharmacol. 1994, 111, 213-218; Corsi, M. et al., Br. J. Pharmacol. 1991, 104, 719-725). In the central nervous system, the 5-HT.sub.4 receptors are found on neurons of the superior and inferior colliculi and in the hippocampus, and are thought to be involved in areas of the central nervous system affecting anxiety, depression, cognition, substance dependency, schizophrenia, appetite, thermoregulation, and such. In the gastrointestinal tract, the 5-HT.sub.4 receptors are found on neurons, e.g., myenteric plexus, as well as on smooth muscle and secretory cells, and appear to modulate gastrointestinal motility, evoke secretion in the alimentary tract, and stimulate cholenergic excitatory pathways involved in the peristaltic reflex (see Hegde, S. S., 5-HT4 Receptors in the Brain and Periphery; Eglen, R. M., Ed., Springer-Verlag Berlin and R.G. Landes Company Georgetown, Tex., 1998, pp 150-169). In the cardiovascular system, the 5-HT.sub.4 receptors mediate 5-HT induced positive inotrophy and chronotropy in atrial myocytes, e.g., bradyarrhythmia or tachyarrhythmia (see Kaumann, A. et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 1991, 344, 150-159).
Thus, it is clear that 5-HT.sub.4 receptor antagonists will offer distinct therapeutic advantages collectively in efficacy and rapidity of onset, particularly in urinary tract disorders related to autonomic mediation of storage and voiding reflexes. Additionally, because the 5-HT.sub.4 receptors found in other organs, e.g., the heart or gastrointestinal tract, are not essential for basic physiological function, minimal side effects are anticipated with improved tolerability (see Ford, A. P. D. W. and Kava, M. S., supra). The compounds of the present invention provide such advantages.
3. Description of the Related Art
U.S. Pat. No. 5,852,014 and PCT Published Application WO 93/18036 (Gaster et al.) refer to certain condensed indole carboxamide derivatives which are disclosed as having 5-HT.sub.4 receptor antagonist activity useful for treating gastrointestinal, cardiovascular, and CNS disorders.
U.S. Pat. No. 5,763,458 (Clark et al.) and European Patent EP 0 700 383 B1 refer to certain dihydrobenzodioxine-propan-1-one derivatives which are disclosed as 5-HT.sub.4 ligands.
U.S. Pat. Nos. 5,741,801 and 5,872,134, and PCT Published Application WO 94/27987 (King et al.) refer to certain dihydrobenzodioxine-propan-1-one derivatives which are disclosed as having 5-HT.sub.4 receptor antagonist activity useful for treating gastrointestinal, cardiovascular or CNS disorders.
U.S. Pat. No. 5,708,174 and PCT Published Application WO 94/08994 (King et al.) refer to certain heterocyclic carboxylate derivatives which are disclosed as having 5-HT.sub.4 receptor antagonist activity useful for treating gastrointestinal, cardiovascular, and CNS disorders.
U.S. Pat. No. 5,705,509 and PCT Published Application WO 94/17071 (Gaster et al.) refer to certain heterocyclic carboxylate derivatives which are disclosed as having 5-HT.sub.4 receptor antagonist activity useful for treating gastrointestinal, cardiovascular, and CNS disorders.
U.S. Pat. No. 5,705,498 and PCT Published Application WO 94/10174 (Gaster et al.) refer to certain dihydrobenzodioxine carboxamide derivatives which are disclosed as being useful in manufacturing medicaments for 5-HT.sub.4 receptor antagonists.
U.S. Pat. Nos. 5,654,320 and 5,798,367 (Catlow et al.) refer to certain indazole carboxamide derivatives which are disclosed as having 5-HT.sub.4 receptor partial agonist and antagonist activity.
U.S. Pat. Nos. 5,620,992 and 5,786,372, and PCT Published Application WO 94/05654 (King et al.) refer to certain dihydrobenzodioxine carboxylate derivatives which are disclosed as having 5-HT.sub.4 receptor antagonist activity.
U.S. Pat. No. 5,580,885 and PCT Published Application WO 93/05038 (King et al.) refer to certain dihydrobenzodioxine carboxamide derivatives which are disclosed as having 5-HT.sub.4 receptor antagonist activity.
U.S. Pat. Nos. 5,374,637, 5,521,314, 5,536,733, 5,552,553, 5,554,772, 5,565,582, 5,576,448, 5,602,129, 5,610,157, 5,616,583, 5,616,738, and 5,739,134, and European Patent EP 0 389 037 B1, (Van Daele et al.) refer to certain dihydrobenzodioxine carboxamide derivatives which are disclosed as having gastrointestinal motility stimulating properties.
U.S. Pat. Nos. 5,185,335 and 5,262,418 (Van Daele et al.) refer to certain dihydrobenzodioxine carboxamide derivatives which are disclosed as having gastrointestinal motility stimulating properties.
PCT Published Application WO 98/27058 (Bromidge et al.) refers to certain benzamide derivatives which are disclosed as having 5-HT.sub.6 receptor activity.
PCT Published Application. WO 96/05166 (assigned to Yamanouchi) refers to certain heterocyclic-substituted alkyl-heterocycloalkylamine derivatives which are disclosed as having 5-HT.sub.4 receptor agonist activity useful for treating CNS disorders and digestive tract movement.
PCT Published Application WO 94/29298 (Gaster et al.) refer to certain dihydrobenzodioxine carboxylate derivatives which are disclosed as having 5-HT.sub.4 receptor antagonist activity useful for treating gastrointestinal, cardiovascular, and CNS disorders.
PCT Published Application WO 94/08995 (Gaster et al.) refers to certain heterocyclic carboxamide derivatives which are disclosed as having 5-HT.sub.4 receptor antagonist activity useful for treating gastrointestinal, cardiovascular, and CNS disorders.
PCT Published Application WO 93/16072 (King et al.) refers to certain heterocyclic carboxamide derivatives which are disclosed as having 5-HT.sub.4 receptor antagonist activity useful for treating gastrointestinal, cardiovascular, and CNS disorders.
PCT Published Application WO 93/03725 (King et al.) refers to certain heterocyclic carboxamide derivatives which are disclosed as having 5-HT.sub.4 receptor antagonist activity.
Japanese Patent Application JP 11001472 (assigned to Dainippon Pharm) refers to certain benzamide derivatives which are disclosed as having 5-HT.sub.4 receptor antagonist activity useful for the prevention and treatment of digestive disorders.
Japanese Patent Application JP 9241241 (assigned to Morishita Roussel) refers to certain N-(1-substituted-4-piperidyl)benzamide derivatives which are disclosed as being selective 5-HT.sub.4 receptor inhibitors useful for treating chronic gastritis, CNS disorders and urological diseases.
Clark, R. D., 5-HT4 Receptors in the Brain and Periphery; Eglen, R. M., Ed., Springer-Verlag Berlin and R.G. Landes Company Georgetown, Tex., 1998, pp 1-48, refers to the medicinal chemistry of certain 5-HT.sub.4 receptor ligands.
Clark, R. D. et al., Bioorganic & Medicinal Chem. Letters. 1995, 5(18), 2119-2122, refers to certain benzodioxanyl ketone derivatives having 5-HT.sub.4 receptor antagonist activity.
Clark, R. D. et al., Bioorganic & Medicinal Chem. Letters. 1994, 4(20) 2477-2480, refers to certain benzoate derivatives having 5-HT.sub.4 partial agonist activity.
All publications, patents, and patent applications cited herein, whether supra or infra, are each hereby incorporated by reference in their entirety.